Porphine (1, Chart 1) is the simplest porphyrin and represents the core macrocycle of naturally occurring and synthetic porphyrins. Accordingly, porphine has been the subject of various experimental and theoretical studies as a benchmark compound in porphyrin chemistry.1 Due to the presence of 8 open β-pyrrole sites and 4 meso sites, porphine is a potential building block for the elaboration of porphyrin derivatives. In this regard, porphine undergoes selective mono-bromination at a β-position to give 2-bromoporphine, whereas the zinc chelate (Zn-1) undergoes reaction at a meso-position to give zinc(II) 5-bromoporphine.3 On the other hand, Shi and Wheelhouse showed that the magnesium(II) chelate of porphine (Mg-1) undergoes tetrabromination to give magnesium(II) meso-tetrabromoporphine. Subsequent palladium-coupling reactions afforded the corresponding tetraaryl A4-porphyrins, which included target porphyrins that are not easily available by other routes (e.g., with heterocyclic substituents).2 Senge has shown that porphine reacts with organolithium reagents to provide meso-substituted A- or cis-A2-porphyrins, which also are difficult to synthesize by other routes.4 In addition, the iron complex of porphine was studied as a simple model of myoglobin.5 These reports provide a glimmer of the possible synthetic utility of porphine; however, the practical use of porphine in synthetic chemistry and biochemistry has been thwarted by two vexing and somewhat interrelated limitations: (1) lack of an efficient method of synthesis of porphine, and (2) extremely low solubility of the free base porphine.

The reported methods for the synthesis of porphine over the past 70 years are summarized in Table 1. Fischer and Gleim obtained 17 mg of porphine by prolonged heating of 20 g of pyrrole-2-carboxaldehyde in formic acid.6 In the same era, Rothemund obtained porphine from pyrrole and formaldehyde, albeit in very low yield (0.02%).7 The yield was increased to 0.9% by slow addition of pyrrole and formaldehyde to propionic acid.8 
A significant improvement was achieved by the use of 2-hydroxymethylpyrrole. Krol increased the yield of porphine up to 5% using 2-hydroxymethylpyrrole in glacial acetic acid containing a catalytic amount of magnesium acetate and potassium persulfate as an oxidizing reagent.9 Other improvements were reported by Adler and Longo (addition of hydroxymethylpyrrole periodically over several days with ethylbenzene as solvent,)10 and by Yalman (use of DMF as a solvent and metal salts afforded porphine in 20%,11 although this yield has subsequently been claimed to be non-reproducible12). Recently, Ellis prepared porphine in a biphasic system in 15.3% yield.12 The use of 1-hydroxypyrrole under micellar conditions afforded porphine in ˜2% yield.13 
In a related approach, N,N-dimethylaminomethylpyrrole has been utilized as a starting material. Copper(II)porphine was prepared from N,N-dimethylaminomethylpyrrole in two steps.14 First, refluxing N,N-dimethylaminomethylpyrrole in chlorobenzene in the presence of ethylmagnesium bromide provided 2,3-dihydroporphine (chlorin) in 3.86% yield. The chlorin was quantitatively converted to copper(II)porphine by heating in acetic acid in the presence of copper(II) acetate. Formation of nickel(II)porphine was also observed as a byproduct in the synthesis of chlorin by simply heating N,N-dimethylaminomethylpyrrole in pyridine in the presence of nickel(II) acetate (yield was not reported).15 
Currently, the most popular method for preparing porphine entails the dealkylation of tetrakis(tert-butylporphyrin) in the presence of strong acid.16,17 The tert-butyl groups can be located at meso- or β-positions. The yield of porphine upon dealkylation of meso-tetra(tert-butyl)porphine is 64-74%; however, this method requires the initial preparation of meso-tetra(tert-butyl)porphine. Porphine also can be prepared by the condensation of tripyrrin with 2,5-bis(hydroxymethyl)pyrrole and subsequent oxidation of the resulting porphyrinogen by p-chloranil in 31% yield.18 
Despite the structural simplicity of porphine, there remains no method of satisfactory yield, scale, and ease of implementation that enables the synthetic capabilities of porphine to be unlocked. The major drawbacks of the existing routes are: (1) low yields of macrocycle formation, which can be compensated in some cases by the use of easily available starting materials (e.g., pyrrole and formaldehyde); (2) low concentration reactions; (3) long reaction times; (4) tedious separation of porphine from the large amount of polymeric material in the crude reaction mixture; and/or (5) lengthy synthetic paths (e.g., five steps from commercially available starting material).